The mechanisms that coordinate the shift from joint homeostasis to osteoarthritis(OA)remain unknown.No pharmacological intervention can currently prevent the progression of osteoarthritis.Accumulating evidence has sho...The mechanisms that coordinate the shift from joint homeostasis to osteoarthritis(OA)remain unknown.No pharmacological intervention can currently prevent the progression of osteoarthritis.Accumulating evidence has shown that subchondral bone deterioration is a primary trigger for overlying cartilage degeneration.We previously found that H-type vessels modulate aberrant subchondral bone formation during the pathogenesis of OA.However,the mechanism responsible for the elevation of H-type vessels in OA is still unclear.Here,we found that PDGFR-βexpression,predominantly in the CD31^(hi)Emcn^(hi) endothelium,was substantially elevated in subchondral bones from OA patients and rodent OA models.A mouse model of OA with deletion of PDGFR-βin endothelial cells(ECs)exhibited fewer H-type vessels,ameliorated subchondral bone deterioration and alleviated overlying cartilage degeneration.Endothelial PDGFR-βpromotes angiogenesis through the formation of the PDGFR-β/talin1/FAK complex.Notably,endothelium-specific inhibition of PDGFR-βby local injection of AAV9 in subchondral bone effectively attenuated the pathogenesis of OA compared with that of the vehicle-treated controls.Based on the results from this study,targeting PDGFR-βis a novel and promising approach for the prevention or early treatment of OA.展开更多
基金This study was supported by the Natural Science Foundation of Guangdong Province,China(2019A1515011614 to ZC)the Science and Technology Program of Guangzhou(202002030483 to ZC)+2 种基金the National Natural Science Foundation of China(81601942 to ZC and 81830079 to BY)the Outstanding Youths Development Scheme of Southern Medical University(2021YQPY008 to ZC)the National Key R&D Program of China(2019YFA0111900 to CL).
文摘The mechanisms that coordinate the shift from joint homeostasis to osteoarthritis(OA)remain unknown.No pharmacological intervention can currently prevent the progression of osteoarthritis.Accumulating evidence has shown that subchondral bone deterioration is a primary trigger for overlying cartilage degeneration.We previously found that H-type vessels modulate aberrant subchondral bone formation during the pathogenesis of OA.However,the mechanism responsible for the elevation of H-type vessels in OA is still unclear.Here,we found that PDGFR-βexpression,predominantly in the CD31^(hi)Emcn^(hi) endothelium,was substantially elevated in subchondral bones from OA patients and rodent OA models.A mouse model of OA with deletion of PDGFR-βin endothelial cells(ECs)exhibited fewer H-type vessels,ameliorated subchondral bone deterioration and alleviated overlying cartilage degeneration.Endothelial PDGFR-βpromotes angiogenesis through the formation of the PDGFR-β/talin1/FAK complex.Notably,endothelium-specific inhibition of PDGFR-βby local injection of AAV9 in subchondral bone effectively attenuated the pathogenesis of OA compared with that of the vehicle-treated controls.Based on the results from this study,targeting PDGFR-βis a novel and promising approach for the prevention or early treatment of OA.
